Abstract
Telomeres protect chromosome ends from fusion, degradation and recombination. Loss of telomere function has opposite effects on tumorigenesis: apoptosis, which inhibits tumour growth, and genomic instability, which accelerates tumour formation. Here we describe a new mechanism by which short telomeres inhibit tumorigenesis through interference with oncogenic translocations. In mice that are null for both ataxia-telangiectasia-mutated (Atm) and telomerase RNA (mTR), the first generation (G1) Atm-/- mTR-/- mice have a lower rate of tumour formation than Atm-/- mTR+/+ mice. These Atm-/- mTR-/- G1 tumours show no increase in either apoptosis or overall genomic instability. Strikingly, the tumours show a high fraction of translocations containing telomere signals at the translocation junctions. Translocations of the T-cell receptors on chromosome 14, which initiate tumorigenesis, were interrupted by fusion with telomeres. Telomere repeats were also detected at the translocation junctions in pre-malignant thymocytes. We propose that telomere fusion to DNA double-strand breaks competes with the generation of oncogenic translocations and thus reduces tumour formation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Age Factors
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Animals
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Apoptosis / genetics
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Ataxia Telangiectasia Mutated Proteins
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B-Lymphocytes / chemistry
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B-Lymphocytes / metabolism
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Body Weight / genetics
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Cell Cycle Proteins / genetics
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Cell Proliferation
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Chromosome Breakage / genetics*
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Crosses, Genetic
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DNA-Binding Proteins / genetics
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Female
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Gene Rearrangement, T-Lymphocyte / genetics
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Genes, T-Cell Receptor / genetics
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Genomic Instability / genetics
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Genotype
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In Situ Hybridization, Fluorescence
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / pathology
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Male
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Mice
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Mice, Knockout
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Mice, SCID
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Models, Genetic
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Neoplasm Transplantation
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Neoplasms, Experimental / genetics*
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Neoplasms, Experimental / pathology
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Protein Serine-Threonine Kinases / genetics
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Spectral Karyotyping
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Survival Analysis
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Telomerase / genetics
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Telomere / genetics
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Telomere / metabolism*
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Translocation, Genetic / genetics*
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Tumor Suppressor Proteins / genetics
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Tumor Suppressor Proteins
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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Telomerase